Combination therapies for cancer

Abstract

Disclosed herein are methods for treating cancer by administering to a subject a composition comprising a bacteriophage expressing a fragment of human aspartate β-hydroxylase (ASPH) and an immune checkpoint protein inhibitor.

1 . A method for inhibiting growth and/or proliferation of cancer cells in a subject, the method comprising administering to the subject an effective amount of a composition comprising a bacteriophage expressing a fragment of human aspartate β-hydroxylase (ASPH) and an effective amount of an immune checkpoint protein inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the cancer cells are prostate, liver, bile duct, brain, head-and-neck, breast, colon, ovarian, cervical, pancreatic or lung cancer cells. 
     
     
         3 . The method of  claim 1 , wherein the cancer cells express human ASPH. 
     
     
         4 . A method for treating or ameliorating cancer or a symptom of cancer in a subject, the method comprising administering to the subject an effective amount of a composition comprising a bacteriophage expressing a fragment of human ASPH and an effective amount of an immune checkpoint protein inhibitor. 
     
     
         5 . The method of  claim 4 , wherein the cancer is prostate, liver, bile duct, brain, head-and-neck, breast, colon, ovarian, cervical, pancreatic or lung cancer. 
     
     
         6 . The method of  claim 5 , wherein the cancer is ASPH-positive squamous cell cancer of the head and neck (SCCHN). 
     
     
         7 . The method of  claim 6 , wherein the SCCHN is locally advanced unresectable SCCHN, metastatic SCCHN or recurrent SCCHN. 
     
     
         8 . The method of  claim 4 , wherein the cancer is a hematologic malignancy. 
     
     
         9 . The method of  claim 4 , wherein the cancer is human ASPH-expressing cancer. 
     
     
         10 . The method of  claim 1 , wherein the bacteriophage is bacteriophage lambda. 
     
     
         11 . The method of  claim 10 , wherein the bacteriophage lambda expresses amino acids 113-311 from the N-terminal region of ASPH fused at the C-terminus of the bacteriophage lambda head decoration protein D (gpD). 
     
     
         12 . The method of  claim 10 , wherein the bacteriophage lambda expresses a fusion protein comprising, in N-terminus to C-terminus order, (1) a gpD fragment, (2) a linker sequence and (3) a fragment of human ASPH. 
     
     
         13 . The method of  claim 12 , wherein the gpD fragment is the amino acid sequence of SEQ ID NO: 2. 
     
     
         14 . The method of  claim 12 , wherein the linker sequence comprises SEQ ID NO: 3. 
     
     
         15 . The method of  claim 12 , wherein the fragment of human ASPH consists of SEQ ID NO: 4. 
     
     
         16 . The method of  claim 10 , wherein the bacteriophage lambda expresses a protein comprising or consisting of the amino acid sequence of SEQ ID NO: 1. 
     
     
         17 . The method of  claim 1 , wherein the composition comprising a bacteriophage is administered at a dose of about 1×10 11  particles in a 1 ml intradermal injection 
     
     
         18 . The method of  claim 17 , wherein the composition comprising a bacteriophage is administered every 3 weeks ±3 days for 4 doses, then every 6 weeks ±3 days for 6 additional doses, and thereafter every 12 weeks ±3 days for up to 24 months. 
     
     
         19 . The method of  claim 1 , wherein the immune checkpoint protein is Programmed Death-1 (PD-1) or Programmed Death Ligand-1 (PD-L1). 
     
     
         20 . The method of  claim 1 , wherein the immune checkpoint protein inhibitor disrupts the interaction between PD-1 and PD-L1. 
     
     
         21 . The method of  claim 1 , wherein the immune checkpoint protein inhibitor is an antibody or an antibody fragment that targets PD-1. 
     
     
         22 . The method of  claim 21 , wherein the antibody that targets PD-1 is pembrolizumab. 
     
     
         23 . The method of  claim 22 , wherein the pembrolizumab is administered at a dose of about 200 mg as an intravenous infusion over about 30 minutes. 
     
     
         24 . The method of  claim 23 , wherein the pembrolizumab is administered about every 3 weeks. 
     
     
         25 . The method of  claim 1 , wherein the immune checkpoint protein inhibitor is an antibody or an antibody fragment that targets PD-L1. 
     
     
         26 . A method for treating or ameliorating cancer or a symptom of cancer in a subject, the method comprising administering to the subject an effective amount of a composition comprising a bacteriophage expressing a fragment of human ASPH and an effective amount of an immune checkpoint protein inhibitor;
 wherein the composition comprising the bacteriophage comprises bacteriophage lambda expressing a fusion protein comprising or consisting of the amino acid sequence of SEQ ID NO: 1;   wherein the composition comprising the bacteriophage is administered at a dose of about 1×10 11  particles in a 1 ml intradermal injection every 3 weeks ±3 days for 4 doses then every 6 weeks ±3 days for 6 additional doses, thereafter every 12 weeks ±3 days; and   wherein the immune checkpoint protein inhibitor is pembrolizumab, and wherein the pembrolizumab is administered at a dose of about 200 mg as an intravenous infusion over about 30 minutes every 3 weeks.   
     
     
         27 . The method of  claim 26 , wherein the cancer is ASPH-positive head-and-neck cancer. 
     
     
         28 . A composition comprising: a pharmaceutical composition comprising a bacteriophage expressing a fragment of human aspartate β-hydroxylase (ASPH); and a pharmaceutical composition comprising an immune checkpoint protein inhibitor; wherein said pharmaceutical compositions are in separate containers. 
     
     
         29 . The composition of  claim 28 , wherein the bacteriophage is a bacteriophage lambda that expresses a protein comprising or consisting of the amino acid sequence of SEQ ID NO: 1. 
     
     
         30 . The composition of  claim 28 , wherein the immune checkpoint protein is Programmed Death-1 (PD-1) or Programmed Death Ligand-1 (PD-L1).